MODULATION OF THE RECEPTOR GATING MECHANISM AND ALLOSTERIC COMMUNICATION IN IONOTROPIC GLUTAMATE RECEPTORS
Author ORCID Identifier
Date of Graduation
Biochemistry and Molecular Biology
Doctor of Philosophy (PhD)
Ionotropic glutamate receptors (iGluRs) found in mammalian brain are primarily known to mediate excitatory synaptic transmission crucial for learning and memory formation. The family of iGluRs consists of AMPA receptors, NMDA receptors and kainate receptors with each member having distinct physiological role. In the recent years, significant progress has been made in understanding the biophysical, and functional properties of iGluRs. The development of Cryo-EM and X-Ray crystallography techniques have further facilitated in the structural understanding of these receptors. However, the multidomain nature, large size of the protein, complex gating mechanism and inadequate knowledge regarding the conformational dynamics of the receptors during channel gating mechanism have been some of the limiting factors in elucidating the structure-function relation of iGluRs. Thus, to understand the conformational dynamics of iGluR family and correlate to its functional behavior, I have utilized single molecule Forster Resonance Energy Transfer (smFRET) and molecular dynamics simulation and specifically investigated the factors influencing gating mechanism and allosteric communication in heteromeric kainate receptor GluK2/K5 and NMDA receptor GluN1/N2A. Some of the major finding in this dissertation includes subunit arrangement of GluK2/K5 and its dynamics involved in resting and desensitized conditions. For the first time we have identified the conformational changes induced at GluK2 and GluK5 subunits in a heteromer GluK2/K5 when bound to different agonists. Utilizing MD simulations in GluN1/N2A NMDA receptors we have identified the structural pathway regarding the mechanism underlying negative cooperativity and how mutation in the receptor leads to abnormal functional behavior. These findings will allow us to understand the conformational control regarding modulation of receptor function and will serve as a basis for developing subunit and conformation-specific therapeutic drugs that can potentially control the abnormal activity of the receptors linked to several neurological diseases.
smFRET, heteromeric GluK2/K5, MD simulations, structural arrangement, protein dynamics, conformational landscape, negative cooperativity, partial agonism, NMDA receptors, PtoH mutation, partial agonist AMPA